Extended GLP-1 compounds

Abstract

The invention relates to protracted GLP-1 compounds and therapeutic uses thereof.

The invention claimed is: 
     
       1. A glucagon-like peptide (GLP-1) analog having a modification of at least one non-proteogenic amino acid residue in positions 7 and/or 8 relative to the sequence GLP-1(7-37) (SEQ ID No 1), where said analog is acylated with a moiety to the lysine residue in position 37 or 38, and where said moiety comprises at least two acidic groups, wherein one acidic group is attached terminally, and wherein the GLP-1 analog is of formula I 
       
         
           
           
               
               
           
         
         wherein 
         Xaa 7  is L-histidine, imidazopropionyl, α-hydroxy-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, Nα-acetyl-histidine, N α -formyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine or 4-pyridylalanine Xaa 8  is Ala, Gly, Val, Leu, Ile, Thr, Ser, Lys, Aib, (1-aminocyclopropyl)carboxylic acid, (1-aminocyclobutyl)carboxylic acid, (1-aminocyclopentyl)carboxylic acid, (1-aminocyclohexyl)carboxylic acid, (1-aminocycloheptyl)carboxylic acid, or (1-aminocyclooctyl)carboxylic acid; 
         Xaa 16  is Val or Leu; 
         Xaa 18  is Ser, Lys or Arg; 
         Xaa 19  is Tyr or Gln; 
         Xaa 20  is Leu or Met; 
         Xaa 22  is Gly, Glu or Aib; 
         Xaa 23  is Gln, Glu, Lys or Arg; 
         Xaa 25  is Ala or Val; 
         Xaa 26  is Lys, Glu or Arg; 
         Xaa 27  is Glu or Leu; 
         Xaa 30  is Ala, Glu or Arg; 
         Xaa 33  is Val or Lys; 
         Xaa 34  is Lys, Glu, Asn or Arg; 
         Xaa 35  is Gly or Aib; 
         Xaa 36  is Arg, Gly or Lys, or is absent; 
         Xaa 37  is Gly, Ala, Glu, Pro, Lys, Asn or is absent; 
         Z is OH or NH 2    
         B is an acidic group selected from 
       
       
         
           
           
               
               
           
         
         where l is 12, 13, 14, 15, 16, 17, 18, 19 or 20, 
         U′ is a spacer selected from 
       
       
         
           
           
               
               
           
         
         wherein n is 1, 2 or 3 and 
         s is 0, 1, 2, or 3. 
       
     
     
       2. A GLP-1 analog according to  claim 1 , wherein n is 1 or 2, s is 0, 1, or 2. 
     
     
       3. A GLP-1 analog according to  claim 1 , wherein l is 14, 15, 16, 17 or 18. 
     
     
       4. A GLP-1 analog according to  claim 1 , wherein s is 1. 
     
     
       5. A GLP-1 analog according to  claim 1 , wherein l is 16. 
     
     
       6. A GLP-1 analog according to  claim 1 , wherein n is 1. 
     
     
       7. A compound according to  claim 1 , where
 Xaa 7  is His or desamino-histidine; 
 Xaa 8  is Ala, Gly, Val, Leu, Ile, Lys or Aib; 
 Xaa 16  is Val; 
 Xaa 18  is Ser; 
 Xaa 19  is Tyr; 
 Xaa 20  is Leu; 
 Xaa 22  is Gly, Glu or Aib; 
 Xaa 23  is Gln or Glu; 
 Xaa 25  is Ala; 
 Xaa 26  is Lys or Arg; 
 Xaa 27  is Glu; 
 Xaa 30  is Ala or Glu; 
 Xaa 33  is Val; 
 Xaa 34  is Lys or Arg; 
 Xaa 35  is Gly or Aib; 
 Xaa 36  is Arg, Lys, or is absent; 
 Xaa 37  is Gly, Asn or is absent; 
 Z is OH or NH 2 . 
 
     
     
       8. A compound according to  claim 7 , where
 Xaa 7  is His; 
 Xaa 8  is Aib; 
 Xaa 16  is Val; 
 Xaa 18  is Ser; 
 Xaa 19  is Tyr; 
 Xaa 20  is Leu; 
 Xaa 22  is Gly or Glu; 
 Xaa 23  is Gln; 
 Xaa 25  is Ala; 
 Xaa 26  is Arg; 
 Xaa 27  is Glu; 
 Xaa 30  is Ala; 
 Xaa 33  is Val; 
 Xaa 34  is Arg; 
 Xaa 35  is Gly; 
 Xaa 36  is Arg; 
 Xaa 37  is Gly or Asn; 
 Z is OH or NH 2 . 
 
     
     
       9. A GLP-1 analog according to  claim 1 , wherein said GLP-1 analog comprises a modification of position 22 to a Glu. 
     
     
       10. A GLP-1 analog according to  claim 1 , wherein said GLP-1 analog comprises a modification of the N-terminal L-histidine in position 7 of the GLP-1(7-37) sequence. 
     
     
       11. A GLP-1 analog according to  claim 10 , wherein said GLP-1 analog comprises imidazopropionyl 7 , α-hydroxy-histidine 7  or N-methyl-histidine 7 , D-histidine 7 , desamino-histidine 7 , 2-amino-histidine 7 , 13-hydroxy-histidine 7 , homohistidine 7 , N′-acetyl-histidine 7 , α-fluoromethyl-histidine 7 , α-methyl-histidine 7 , 3-pyridylalanine 7 , 2-pyridylalanine 7  or 4-pyridylalanine 7 . 
     
     
       12. A GLP-1 analog according to  claim 1 , wherein said GLP-1 analog comprises a substitution of the L-alanine in position 8 of the GLP-1(7-37) sequence for another amino acid residue. 
     
     
       13. A GLP-1 analog according to  claim 12 , wherein said GLP-1 analog comprises Aib 8 , Gly 8 , Val 8 , Ile 8 , Leu 8 , Ser 8 , Thr 8 , (1-aminocyclopropyl)carboxylic acid, (1-aminocyclobutyl)carboxylic acid, (1-aminocyclopentyl)carboxylic acid, (1-aminocyclohexyl)carboxylic acid, (1-aminocycloheptyl)carboxylic acid, or (1-aminocyclooctyl)carboxylic acid. 
     
     
       14. A GLP-1 analog according to  claim 13 , wherein said GLP-1 analog comprises Aib 8 . 
     
     
       15. A GLP-1 analog according to  claim 1 , wherein said GLP-1 analog comprises no more than 3 amino acid residues which are not encoded by the genetic code. 
     
     
       16. A GLP-1 analog according to  claim 1 , wherein said GLP-1 analog comprises only one lysine residue. 
     
     
       17. A GLP-1 analog according to  claim 1 , wherein said Lysine is in position 38 relative to the sequence GLP-1(7-37) (SEQ ID No 1). 
     
     
       18. A compound according to  claim 1 , which is selected from 
       
         
           
           
               
               
           
         
         [Aib8,Arg26,34]GLP-1(7-37)Lys[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]-OH, 
       
       
         
           
           
               
               
           
         
       
     
     
       19. A method for increasing the time of action in a patient of a GLP-1 analog, said method comprising administering to a patient in need thereof said GLP-1 analog which has been acylated with a moiety B—U′ as disclosed in  claim 1 , on the lysine residue in position 37 or 38 of said GLP-1 analog. 
     
     
       20. A method for increasing the time of action in a patient of a GLP-1 analog to more than about 40 hours, said method comprising administering to a patient in need thereof said GLP-1 analog where at least one of the amino acid residues in positions 7 and 8 of said GLP-1 analog thereof has been modified, and where acylating said GLP-1 analog has been acylated with a moiety B—U′—as disclosed in  claim 1  on the lysine residue in position 37 or 38 of said GLP-1 analog. 
     
     
       21. A pharmaceutical composition comprising a compound according to  claim 1 , and a pharmaceutically acceptable excipient. 
     
     
       22. The pharmaceutical composition according to  claim 21 , which is suited for parenteral administration. 
     
     
       23. A method for treating hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, syndrome X, dyslipidemia, cognitive disorders, atheroschlerosis, myocardial infarction, coronary heart disease and other cardiovascular disorders, stroke, inflammatory bowel syndrome, dyspepsia and/or gastric ulcers in a subject, said method comprising administering to a subject in need of such treatment an effective amount of a GLP-1 analog according to  claim 1 . 
     
     
       24. A method for delaying disease progression in type 2 diabetes in a subject, said method comprising administering to a subject in need of such treatment an effective amount of a GLP-1 analog according to  claim 1 . 
     
     
       25. A method for decreasing food intake, decreasing β-cell apoptosis, increasing β-cell function and β-cell mass, and/or for restoring glucose sensitivity to β-cells in a subject, said method comprising administering to a subject in need of such treatment an effective amount of a GLP-1 analog according to  claim 1 .